Hippocampal neurogenesis declines in old age. As newly added neurons participate in hippocampal- dependent learning and memory functions, age-related decrease in neurogenesis is believed to contribute to cognitive dysfunction observed in the elderly. While aging does not reduce the numbers of putative hippocampal neural stem/progenitor cells (NSCs) or impair neuronal differentiation and survival of newly born cells, the percentage of quiescent NSCs increases in the aged hippocampus. In this context, identification of safe dietary supplements that have the ability to stimulate the quiescent NSCs to produce new neurons in the aged hippocampus has immense value for promoting improved cognitive function in the elderly. Resveratrol, a phytoalexin found in the skin of red grapes with potent antioxidant and anti- inflammatory properties, strikes as a potential dietary supplement for improving neurogenesis in the aged hippocampus because of the perceived link between reductions in NSC plasticity and increases in reactive oxygen species and inflammation during aging. Moreover, after the awareness of reduced cardiac risk in the consumers of Resveratrol-containing red wine, Resveratrol is being promoted as a dietary supplement for improving cardiovascular health. However, its effects on NSCs and neurogenesis are unknown. We hypothesize that Resveratrol administration in old age promotes hippocampal NSC proliferation and neurogenesis, which in turn leads to improved cognitive function. We propose to address this hypothesis through highly quantitative experiments in the following two specific aims. In Specific Aim 1, we will quantify the efficacy of long-term (28 days) administration of different doses of Resveratrol in aged rats for stimulating the proliferation of NSCs and increasing the extent of hippocampal neurogenesis. In Specific Aim 2, we will ascertain whether long-term administration of Resveratrol would improve learning and memory function in aged rats displaying cognitive dysfunction. We will also determine whether the enhanced cognitive function after Resveratrol treatment in these impaired rats is associated with increased incorporation of newly born neurons into the hippocampal memory circuitry and increased expression of neurogenesis-related genes. These studies are highly relevant towards developing dietary supplement strategies that ease hippocampal-related cognitive impairments in the elderly or in elderly patients with early stage of Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This project will test the efficacy of long-term administration of Resveratrol in cognitively impaired aged rats for stimulating neural stem cell proliferation and improving hippocampal neurogenesis and cognitive function. These studies are relevant towards developing dietary supplement therapies that alleviate cognitive impairments in the elderly or in elderly patients with early stage of Alzheimer's disease.